Srdjan Denic

Consanguinity decreases risk of breast cancer – cervical cancer unaffected

Marriages between third-degree and more distant relatives are common in many parts of the world. Offspring of consanguineous parents have increased morbidity and mortality related to recessive gene disorders. In a population with a high frequency of consanguinity, we examined the frequency of breast cancer (related in part to tumour genes) and cervical cancers (related to virus infection) among offspring of consanguineous and non-consanguineous parents. Study was done prospectively in the United Arab Emirates. Selected were married female citizens, ages 40–65, who attended 12 primary health care clinics for whatever reason. In a face-to-face interview, subjects were asked: (a) about consanguineous marriages in family; (b) if they have or have had breast or cervical cancer; (c) about family history of cancer, cancer screening and other parameters. Tumour diagnosis was confirmed by review of medical records. Of 1750 women invited into study, 1445 (79%) could be used in analysis. Among 579 (40%) women of consanguineous and 866 (60%) of non-consanguineous parents there were 24 and 54 with breast cancer, respectively (RR = 0.66, CI 0.42 – 1.06). In the 40 to 50 age group, breast cancer reported 13 of 446 women of consanguineous and 37 of 633 of non-consanguineous parents (RR = 0.50, Cl 0.27 – 0.93). Cervical cancer had 15 women in consanguineous and 32 in non-consanguineous group (RR = 0.70, Cl 0.38 – 1.28). Number of families with history of breast cancer in consanguineous and non-consanguineous group was 21 and 23, respectively (P = 0.29). The cancer screening rates and other variable values had fairly balanced distribution between the 2 groups. Having consanguineous parents decreases the risk of breast cancer especially in younger women, risk of cervical cancer being unaffected.

Acute Thrombocytopenia, Leucopenia, and Multiorgan Dysfunction: The First Case of SFTS Bunyavirus outside China?

We report a 57-year-old man with acute thrombocytopenia, leucopenia, and multiorgan dysfunction. Patient was from North Korea and was temporarily working in Dubai, United Arab Emirates, when he fell ill in March 2009. At the same time and unknown to us, many patients with similar clinical manifestations were admitted to hospitals in China. The Chinese cases—identified between March and July 2009—were recently reported to have been infected with a tick-born strain of bunyavirus, a new disease. The virus infection was documented in patients from central China and the region that shares the border with North Korea. The clinical manifestations, the time of disease onset, and geographical link of the patient with the region in which the disease is endemic suggest that the patient had SFTS bunyavirus infection.

Genetic benefits of consanguinity through selection of genotypes protective against malaria

ABSTRACT Consanguineous marriages are usually socially driven and can be genetically harmful. The detrimental effects of inbreeding are the consequence of homozygosity of harmful genes. On the other hand, beneficial effects of inbreeding, theoretically, could be expected in those who are homozygous for protective recessive and codominant genes. Here, we argue that the most common monogenetic conditions in humans, namely, α-thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobin C, and Duffy antigen negative red blood cells, which have evolved under pressure from malaria, had their survival and selection enhanced by consanguineous marriages in malaria-infested regions of the world. This hypothesis is supported by several observations. First, the presence of two mutations in homozygotes involving the listed conditions (except G6PD deficiency) imparts better protection against malaria than the presence of one or no mutation (heterozygous or normal genotypes, respectively); consanguinity increases the number of homozygotes, especially at low allele frequency. For G6PD deficiency, inbreeding could increase the allele frequency of the G6PD-deficient allele. Second, there is overlap between, on the one hand, the geographic distributions of malaria, thalassemias, and other red blood cell conditions that protect against malaria and, on the other hand, consanguineous marriages. Third, the distribution of different intensities of malaria infestation is matched with the frequency of human inbreeding. These observations, taken together, offer strong support to the hypothesis that the culture of consanguineous marriages and the genetics of protection against malaria have co-evolved by fostering survival against malaria through better retention of protective genes in the extended family.

Consanguineous marriages and endemic malaria: can inbreeding increase population fitness?

BackgroundThe practice of consanguineous marriages is widespread in countries with endemic malaria. In these regions, consanguinity increases the prevalence of α+-thalassemia, which is protective against malaria. However, it also causes an excessive mortality amongst the offspring due to an increase in homozygosis of recessive lethal alleles. The aim of this study was to explore the overall effects of inbreeding on the fitness of a population infested with malaria.MethodsIn a stochastic computer model of population growth, the sizes of inbred and outbred populations were compared. The model has been previously validated producing results for inbred populations that have agreed with analytical predictions. Survival likelihoods for different α+-thalassemia genotypes were obtained from the odds of severe forms of disease from a field study. Survivals were further estimated for different values of mortality from malaria.ResultsInbreeding increases the frequency of α+-thalassemia allele and the loss of life due to homozygosis of recessive lethal alleles; both are proportional to the coefficient of inbreeding and the frequency of alleles in population. Inbreeding-mediated decrease in mortality from malaria (produced via enhanced α+-thalassemia frequency) mitigates inbreeding-related increases in fatality (produced via increased homozygosity of recessive lethals). When the death rate due to malaria is high, the net effect of inbreeding is a reduction in the overall mortality of the population.ConclusionConsanguineous marriages may increase the overall fitness of populations with endemic malaria.

Screening for cervical cancer among Arab women

A cross-sectional community-based survey was conducted from August 1999 to February 2000 on native women of the United Arab Emirates to examine the knowledge attitudes barriers and practices related to cervical cancer screening. The study included married women aged 40-65 from 12 primary health care clinics. Qualified nurses interviewed the subjects and questionnaires were administered during face-to-face interviews with a health educator. The results showed that 15.4% had had a Papanicolau (Pap) test for early detection of cancer. In addition the frequency of screening for cervical cancer was associated with age employment type of area of residence and number of clinic visits. On the other hand factors such as being employed living in a semi-urban area and a smaller annual number of clinic visits were independent predictors of having a Pap test. The study also showed that 97% preferred having female health personnel administer the Pap test. Overall the rate of Pap tests is low among Arab women which is attributed to the infrequent offer of such screening.

Consanguinity as risk factor for cervical carcinoma.

Cervical carcinoma is caused by human papillomavirus (HPV). Among the risk factors for HPV infection are having multiple sex partners and sex partners who themselves had multiple sex partners. Women married to relatives are more likely to become infected with HPV and develop cervical carcinoma. Consanguineous spouses have a mild sexual aversion to each other that leads to sex avoidance and increases likelihood of satisfying sexual desire outside the marriage. Sexual aversion develops as a result of spouses growing together in early childhood, which triggers biological imprinting of Westermarck. Westermarcks effect prevents incest in nuclear family. In consanguineous family, it extends to spouses, producing mild sexual antipathy. Because of high prevalence of consanguinity worldwide, it is important to test this hypothesis.

On Some Novel Aspects of Consanguineous Marriages

Consanguineous marriages, often viewed as incestuous and objectionable, are more widespread than commonly perceived. They integrate multiple facets of human adaptation: economic, cultural and genetic. The widely touted explanation for the origin and persistence of consanguinity is that it provides many socioeconomic benefits; however, this view may be too simplistic. The bias against consanguinity may preclude an objective understanding of this sociobiological puzzle. Inbreeding increases the speed of selection of beneficial recessive and co-dominant alleles, e.g. those that protect against diseases. In populations endemic with malaria, the prevalence of consanguineous marriages and the frequency of alleles protective against malaria are both very high. Thus, consanguinity could theoretically increase the relative fitness of a population under specific ecological conditions; sometimes, the overall genetic benefits may exceed genetic costs of inbreeding. We discuss some recent evidence from studies on inbreeding along with the reasons responsible for the mating strategy found in some human populations. We contend that a better appreciation of our inherent biases and potential genetic benefits of inbreeding in specific ecological conditions would help us to appreciate the wider picture of consanguinity.

Hemoglobin A2 Lowered by Iron Deficiency and α-Thalassemia: Should Screening Recommendation for β-Thalassemia Change?

Screening for β-thalassemia trait (BTT) relies on measuring hemoglobin (Hb) A2. Since multiple factors can affect HbA2 levels, the screening can become unreliable. In 1356 healthy Arabs enrolled into a federally funded premarital BTT screening program, the effects of iron deficiency (ID), α +-thalassemia trait, gender, smoking, and tribalism on HbA2 were studied. The complete blood count and hemoglobin fractions were determined on the entire cohort; serum ferritin (<15 μg/L) in 391 subjects was used to determine ID. BTT was present in 29 (2.1%) subjects (HbA2 > 3.5%). Among 77(20.3%) subjects with ID, the mean HbA2 (2.30 ± 0.23%) was 0.2% lower than in subjects without iron deficiency (2.50 ± 0.24%, P < 0.0001). In 65 (38%)/172 subjects with phenotypic α +-thalassemia trait, the mean HbA2 (2.43 ± 0.24%) was 0.13% lower than in subjects without α +-thalassemia trait, P < 0.0001. The mean HbA2 did not differ between males and females, smokers and nonsmokers, and between the tribes. Thus, 35 (2.6%) subjects with HbA2 between 3.2 and 3.5% were at a risk of false negative diagnosis of BTT. Since iron deficiency and α +-thalassemia are both common and both lower HbA2, modifications in screening recommendations for BTT are proposed.

β-Thalassemia in Abu Dhabi: Consanguinity and Tribal Stratification are Major Factors Explaining the High Prevalence of the Disease

Tribalism and consanguineous marriages are common in parts of the world with a high prevalence of the β-thalassemia (β-thal) mutations, and increase the risks of homozygosity for this and other recessive disorders. We explored the frequency of β-thal genes and β-thal carriers in 5672 subjects screened before marriage, of whom 2262 were couples. The mean coefficient of inbreeding (F) in the population was estimated from self-reported relationships to prospective spouses in 383 subjects. Overall frequency of β-thal mutations and β-thal carriers in the population were 1.16 and 2.3%, respectively. Among the 14 largest tribes, β-thal carrier frequencies varied from 0 to 13.6%. The estimated F in the population was 0.022. The expected number of couples needed to be screened to detect one couple who were both β-thal carriers in the non inbreeding (F = 0) and inbreeding (F = 0.022) population was 1858 and 646, respectively. However, among 2262 couples, 10 were both β-thal carriers, i.e., 1 in 226 couples, significantly (p = 0.02) more than expected by taking only inbreeding into account. Although β-thal mutations are relatively rare, the burden of β-thal disease is increased eight-fold by tribalism and consanguinity.

Consanguinity affects selection of alpha-thalassemia genotypes and the size of populations under selection pressure from malaria

Background: In populations with α+-thalassemia gene deletion, the practice of consanguineous marriages is common. Aim: The study explored the impact of consanguinity (inbreeding) on the selection of α+-thalassemia genotypes in a computer model. Method: In a population under selection pressure from malaria, a single protective mutation (–α/αα genotype) was introduced among normal genotypes (αα/αα), and mating allowed to proceed. Heterozygote (–α/αα) and homozygote (–α/–α) children were 1.5 and 2.5 times more likely to survive malaria than those with normal genotypes. Using different coefficients of inbreeding (F, range 0–0.12), we examined the effect of population size, and the mean number of generations required for the homozygote frequency to reach 0.5. Results: On average, consanguineous populations were larger than randomly mating populations and the size was directly proportional to F. In more inbred populations,–α/–α homozygotes reached a frequency of 0.5 faster than in less inbred populations. As the frequency of the α+-thalassemia allele in a population increases, however, the positive effect of inbreeding on the population growth decreases. Conclusion: Under selection pressure from malaria, consanguinity may increase the speed of selection of–α/–α homozygotes and provide an advantage regarding population growth over non-consanguineous populations.